Medical angiographic imaging typically involves administration of a detectable substance to a subject (see U.S. Pat. No. 6,915,154). In some instances the detectable substance may also be a therapeutic agent (see U.S. Patent Publication No. 2004/0206364). Most often the detectable substance is administered directly to a subject by intravascular injection, in which case the detectable substance mixes with and is carried through the vasculature by plasma, along with the blood cells. When using conventional angiography methodology, wherein the detectable substance is a liquid dye, blood flow physiology is treated too simplistically, especially at the microvascular level (i.e., the arterioles, capillaries, and venules).
Blood is a shear-thinning, non-Newtonian fluid. However, in diagnostic applications, blood often is treated as if it were water-like (i.e., a Newtonian fluid), and not an homogeneous mixture of two distinctly different non-Newtonian fluids: (1) liquid (plasma) and (2) particles (blood cells, especially erythrocytes). Limitations inherent in conventional angiography contribute to ignoring that the dynamics of plasma movement do not necessarily reflect the dynamics of erythrocyte movement, especially at the microvascular level where their movement is far more important to the circulation's metabolic efficiency than that of plasma. For example, in conventional sodium fluorescein and indocyanine green angiography (SFA and ICGA) of the ocular vasculatures, observed fluorescence arises from dye molecules associated primarily with blood plasma, not erythrocytes. Even in capillaries, where they deform in order to pass through one-at-a-time in boxcar fashion, erythrocytes cannot be seen in conventional angiogram images, so metabolically significant phenomena such as vasomotion, which results in periodic suspension of erythrocyte movement through individual capillaries, cannot be directly visualized. Yet, it has been postulated that all the clinical findings concerning edema in diabetic maculopathy can be explained as a result of disturbances in retinal vasomotion (Bek 1999, Acta Ophthalmol Scand 77:376). Moreover, in conventional angiography, dye molecules leave the plasma and become associated with vessel walls, so those blood vessels rapidly exhibit steady-state fluorescence, thereby obscuring further visualization of blood movement. Consequently, conventional fluorescent dye angiography is limited as a diagnostic tool, since what hemodynamic information it conveys is misleading with respect to metabolic efficiency and capacity of microvascular blood flow. An example of this would be relying on observation of conventional angiograms to assay the metabolic capacity of blood flow through a choroidal neovascular (CNV) membrane. Due to the well-known phenomenon of plasma skimming (likely to occur where the CNV feeder vessel arises at an acute angle from the choroidal arterial vessel feeding it), only erythrocyte-deficient plasma would profuse the CNV, but this deficiency would not be reflected in the angiogram images since the fluorescence arises only from dye in the plasma, not the erythrocytes.
Alternatively, a detectable substance (e.g., sodium fluorescein dye) has been administered in a particle carrier, heat sensitive liposomes (Kiryu et al. 1994, Invest Opthalmol Vis Sci 35:3724). However, such artificial particles are rigid and are small to assure that they can pass unobstructed through the smallest capillary vessels. They may not serve as faithful models of erythrocyte dynamics.